GENETIC VARIATION AND ITS ROLE
IN HEALTH AND PHARMACOLOGY
PRESENTED BY:-GAGANDEEP JAISWAL
(M. PHARM. PHARMACOLOGY) 1
Department of Pharmaceutical Sciences And Technology,MRSPTU
• Genetic variation:- In a very simple language, genetic variation is a measure of the
variation that exists in the genetic makeup of individuals within population.
variation in alleles of genes that occurs both within and among populations
• Genetic Diversity: the level of biodiversity, refers to the total number of genetic
characteristics in the genetic makeup of a species
• Crossing Over: the exchange of genetic material between homologous
chromosomes that results in recombinant chromosomes
• Phenotypic Variation: variation (due to underlying heritable genetic variation); a
fundamental prerequisite for evolution by natural selection
• Genetic Variation: variation in alleles of genes that occurs both within and among
• Alleles:-each of two or more alternative forms of a gene that arise by mutation and
are found at the same place on a chromosome.
• Natural Selection:- the process whereby organisms better adapted to their
environment tend to survive and produce more offspring. The theory of its action
was first fully expounded by Charles Darwin, and it is now regarded as be the main
process that brings about evolution.
WHAT IS GENETIC VARIATION?
Genetic variation generally refers to the differences in genes between individual
members of a population, or the frequency in which the various gene types are
expressed. Genetic variation is incredibly important for the survival and adaptation
of a species, as it helps in terms of natural selection and evolution.
Individuals of a species have similar characteristics but they are rarely identical, the
difference between them is called variation.
In genetic variation, the genes of organisms within a population change.
Gene alleles determine distinct traits that can be passed on from parents to
offspring. Gene variation is important to the process of natural selection. The
genetic variations that arise in a population happen by chance, but the process of
natural selection does not.
GENE ALLELES DETERMINES THE DISTINCT
TRAITS OF AN INDIVIDIUAL
Sources of Genetic Variation
• Gene duplication, mutation, or other processes can
produce new genes and alleles and increase genetic
variation. New genetic variation can be created within
generations in a population, so a population with rapid
reproduction rates will probably have high genetic
variation. However, existing genes can be arranged in new
ways from chromosomal crossing over and recombination
in sexual reproduction. Overall, the main sources of genetic
variation are the formation of new alleles, the altering of
gene number or position, rapid reproduction, and sexual
Causes of Genetic Variation
• Genetic variation occurs mainly through DNA mutation,
gene flow , crossing over and sexual reproduction. Due to
the fact that environments are unstable, populations that
are genetically variable will be able to adapt to changing
situations better than those that do not contain genetic
variation. Gene flow and sexual reproduction reshuffle
alleles within a population, giving offspring combinations
which differ from their parents and from others.
Nonrandom Mating and Environmental Variance are some
other factors which leads to the genetic variation.
Causes In Detail
A. DNA Mutation:-Mutations are changes to an organism’s DNA and
are an important driver of diversity in populations. Species evolve
because of the accumulation of mutations that occur over time.
The appearance of new mutations is the most common way to
introduce novel genotypic and phenotypic variance. Some
mutations are unfavorable or harmful and are quickly eliminated
from the population by natural selection. Others are beneficial
and will spread through the population. Whether or not a
mutation is beneficial or harmful is determined by whether it
helps an organism survive to sexual maturity and reproduce.
Some mutations have no effect on an organism and can linger,
unaffected by natural selection, in the genome while others can
have a dramatic effect on a gene and the resulting phenotype.
Mutation in a garden rose: A mutation has caused this garden moss rose to produce
flowers of different colors. This mutation has introduce a new allele into the
population that increases genetic variation and may be passed on the next generation.9
B. Gene Flow:-An important evolutionary force is gene flow: the flow of
alleles in and out of a population due to the migration of individuals or
gametes. While some populations are fairly stable, others experience
more movement and fluctuation.
Many plants, for example, send their pollen by wind, insects, or birds to
pollinate other populations of the same species some distance away. Even
a population that may initially appear to be stable, such as a pride of lions,
can receive new genetic variation as developing males leave their mothers
to form new prides with genetically-unrelated females.
This variable flow of individuals in and out of the group not only changes
the gene structure of the population, but can also introduce new genetic
variation to populations in different geological locations and habitats.
Maintained gene flow between two populations can also lead to a
combination of the two gene pools, reducing the genetic variation
between the two groups. Gene flow strongly acts against speciation, by
recombining the gene pools of the groups, and thus, repairing the
developing differences in genetic variation that would have led to full
speciation and creation of daughter species.
For example, if a species of grass grows on both sides of a highway, pollen
is likely to be transported from one side to the other and vice versa. If this
pollen is able to fertilize the plant where it ends up and produce viable
offspring, then the alleles in the pollen have effectively linked the
population on one side of the highway with the other. 10
Gene flow: Gene flow can occur when an individual travels from one
geographic location to another. 11
C. Crossing over and sexual reproduction:-
Chromosomal crossover (or crossing over) is the
exchange of genetic material between 2 homologous
chromosomes non-sister chromatids that results in
recombinant chromosomes during sexual
reproduction. Crossing over accounts for genetic
variation, because due to the swapping
of genetic material during crossing over, the
chromatids held together by the centromere are no
longer identical. Sexual reproduction promotes
genetic variation by producing different gene
combinations. Meiosis is the process by which sex
cells or gametes are created. Genetic variation occurs
as alleles in gametes are separated and randomly
united upon fertilization.
Crossing over and recombination during meiosis
Nonrandom Mating and Environmental Variance
Population structure can be altered by nonrandom mating (the preference
of certain individuals for mates) as well as the environment.
Nonrandom mating can occur when individuals prefer mates with
particular superior physical characteristics or by the preference of
individuals to mate with individuals similar to themselves.
Assortative mating in the American
Robin: The American Robin may practice
assortative mating on plumage color, a
melanin based trait, and mate with other
robins who have the most similar shade
of color. However, there may also be
some sexual selection for more vibrant
plumage which indicates health and
• Genes are not the only players involved in determining
population variation. Phenotypes are also influenced by other
factors, such as the environment.
determination: The sex of the
American alligator (Alligator
mississippiensis) is determined
by the temperature at which
the eggs are incubated. Eggs
incubated at 30 degrees C
produce females, and eggs
incubated at 33 degrees C
Genetic variation in the shells of Donax variabilis: An enormous
amount of phenotypic variation exists in the shells of Donax varabilis16
Human genetic variation
• Human genetic variation is the genetic differences in and among populations.
• There may be multiple variants of any given gene in the human population
(alleles), a situation called polymorphism.
• No two humans are genetically identical. Even monozygotic twins (who develop
from one zygote) have infrequent genetic differences due to mutations occurring
• The study of human genetic variation has evolutionary significance and medical
applications. It can help scientists understand ancient human population
migrations as well as how human groups are biologically related to one another.
• For medicine, study of human genetic variation may be important because some
disease-causing alleles occur more often in people from specific geographic
regions. New findings show that each human has on average 60 new mutations
compared to their parents.
Role of genetic variation in health and pharmacology
• Differences in allele frequencies contribute to group differences in the incidence of
some monogenic diseases, and they may contribute to differences in the incidence
of some common diseases. For the monogenic diseases, the frequency of
causative alleles usually correlates best with ancestry, whether familial (for
example, Ellis-van Creveld syndromeamong the Pennsylvania Amish), ethnic (Tay-
Sachs disease among Ashkenazi Jewish populations), or geographical
(hemoglobinopathies among people with ancestors who lived in malarial regions).
To the extent that ancestry corresponds with racial or ethnic groups or subgroups,
the incidence of monogenic diseases can differ between groups categorized by race
or ethnicity, and health-care professionals typically take these patterns into
account in making diagnoses.
• Some other variations on the other hand are beneficial to human, as they prevent
certain diseases and increase the chance to adapt to the environment. For
example, mutation in CCR5 gene that protects against AIDS. CCR5 gene is absent on
the surface of cell due to mutation. Without CCR5 gene on the surface, there is
nothing for HIV viruses to grab on and bind into. Therefore the mutation on CCR5
gene decreases the chance of an individual’s risk with AIDS. The mutation in CCR5
is also quite popular in certain areas, with more than 14% of the population carry
the mutation in Europe and about 6-10% in Asia and North Afriac.
HIV Attachment 19
• Apart from mutations, many genes that may have aided humans in ancient
times plague humans today. For example, it is suspected that genes that
allow humans to more efficiently process food are those that make people
susceptible to obesity and diabetes today.
• As far as pharmacological role of genetic variation is concerned, Variability
in drug efficacy and adverse effects are observed in clinical practice
• Drug-related genes show high extent of genetic variability across millions of
• Cancer drug target genes have many germ line functional-variants:-
Especially in cancer therapy, genetic variation in drug targets has been
recognized to play a crucial role for treatment success. While some cancer
drugs do not act in the tumor tissue, the cancer drug’s primary site of
action usually is in the tumor, whose genome contains tumor specific
somatic variants as well as a subset of patient-specific germ line variants30.
Information on somatic variants from tumor samples is thus increasingly
used to enable research on drug design and to implement stratified or
personalized cancer therapy.
• For instance, the DRPs of taxanes (docetaxel, paclitaxel, and cabazitaxel) are
30 percentage points higher in the cohorts of South Asian and European
ancestry compared to the cohort of African ancestry (DRPSAS/NFE = 85% vs
DRPAFR = 45%) due to functional variants in the four taxane
targets, TUBB1, MAP2, MAP4, and MAPT.
• Dopamine D2 (encoded by the DRD2 gene) receptors are primarily
expressed in the terminal regions of dopaminergic neurons. Studies in
DRD2-null mice suggest that the D2 receptor functions as an auto receptor
on dopamine neurons. The most well-established polymorphism in the
DRD2 gene is Taq1A, a C>T substitution located 10kb (kilobases)3’ of the
DRD2 gene. This Taq1A polymorphism is associated with an increased risk
for multiple types of substance abuse , including heroin use , cocaine
dependency , psychostimulant polysubstance abuse , and smoking.
• In addition to the dopaminergic system, nicotinic acetylcholine receptors
have been implicated in nicotine reward and dependency. Two non
synonymous SNPs on exon5 (rs1044396/1629G>T
andrs1044397/1659G>A)of the gene encoding for the α4 subunit of the
nicotinic acetylcholine receptor (CHRNA4) were associated with a lower risk
of nicotine dependency in Chinese men (96), which was recently replicated
in a European population. A G>A variant, rs2236196, in the 3 untranslated
region of CHRNA4, was associated with greater subjective effects of
nicotine and higher risk of nicotine dependency.
IS GENETIC DIVERSITY GOOD OR BAD?
Genetic diversity is, in general, a good thing for a population, for a simple reason:
adaptation via natural selection depends on the existence of variation (there cannot
be selection in the absence of alternatives). Other things being equal, a population
possessing a greater amount of genetic diversity has a greater probability of
already possessing adaptive alleles that might be necessary to meet new
environmental challenges (e.g., pathogens).
Even the boundaries between the useful/neutral/deleterious categories are blurred.
Deleterious anaemia-causing mutations are known to have benefits of malaria-
Neutral variants may be “useful” ones in waiting: for example, lactase persistent
mutants may have existed in the human species for hundreds of thousands of years,
appearing and re-appearing by mutation, but it is when they encountered cow’s
milk and the need to drink it that they shifted from “neutral” to “useful”.
And, even useful alleles can cease to be so, e.g., the eradication of swamps and
malaria in Greece has removed the benefit of malaria-resistence, and left only the
harm of anaemia.
a Availability of documented pharmacogenetic associations for 1236 FDA-approved drugs in public repositories such as the PharmGKB database  (left) is less abundant than functional variants observed in the population for the drug target genes (right). b, c Examples of known and novel genetic variants (green) in the target genes of warfarin and taxanes that could affect drug efficacy due to effects on the binding site (ligand highlighted in orange)